{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:55:50Z","timestamp":1792166150183,"version":"4.4.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2012,2,9]],"date-time":"2012-02-09T00:00:00Z","timestamp":1328745600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We report a 55-year-old woman who suffered atypical subtrochanteric femoral fractures (ASFFs) after 4 years of exposure to alendronate and then zolendronate given for \u201costeoporosis.\u201d Before alendronate treatment, she had low bone mineral density. After several months of therapy, metatarsal stress fractures began. Bisphosphonate (BP) administration was stopped following the ASFFs, and the adult form of hypophosphatasia (HPP) was diagnosed from low serum alkaline phosphatase (ALP) activity, high endogenous levels of two natural substrates for the \u201ctissue-nonspecific\u201d isoenzyme of ALP (TNSALP), and a heterozygous mutation within the gene that encodes this enzyme. Experience with other HPP families showed that her mutation (Arg71His) with a second defective TNSALP allele can cause severe HPP in infancy, and when heterozygous can cause mild HPP featuring premature loss of deciduous teeth in children. Because the skeletal disease of HPP results from extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi) and its inhibitory effect on mineralization, perhaps HPP patients or carriers will have adverse effects from BPs. BPs are analogues of PPi and can suppress bone turnover but also deactivate TNSALP. Our report is the first of BP exposure preceding ASFFs in adult HPP. To explore a potential role for TNSALP deactivation in ASFFs, mutation analysis of TNSALP should be studied in a cohort of these patients. Meanwhile, clinicians must suspect HPP when clinical or laboratory clues include premature loss of primary dentition, pseudofractures or recurrent poorly healing metatarsal stress fractures, a family history suggestive of HPP, or low serum ALP activity. If HPP is documented, BP treatment might be avoided. To establish the diagnosis of HPP, assays for two natural substrates for TNSALP and TNSALP mutation analysis are available in commercial laboratories. With positive findings, radiological or bone biopsy evidence of acquired osteomalacia would indicate the adult form of this inborn-error-of-metabolism. \u00a9 2012 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.1565","type":"journal-article","created":{"date-parts":[[2012,2,9]],"date-time":"2012-02-09T15:00:55Z","timestamp":1328799655000},"page":"987-994","source":"Crossref","is-referenced-by-count":173,"title":["\u201cAtypical femoral fractures\u201d during bisphosphonate exposure in adult hypophosphatasia"],"prefix":"10.1093","volume":"27","author":[{"given":"Roger AL","family":"Sutton","sequence":"first","affiliation":[{"name":"Osteoporosis Program, Women's Health Centre, University of British Columbia, Vancouver, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Mumm","sequence":"additional","affiliation":[{"name":"Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA"},{"name":"Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen P","family":"Coburn","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indiana University\u2013Purdue University, Fort Wayne, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L","family":"Ericson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indiana University\u2013Purdue University, Fort Wayne, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P","family":"Whyte","sequence":"additional","affiliation":[{"name":"Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA"},{"name":"Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,2,9]]},"reference":[{"key":"2024020318260091300_bib1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.4158\/EP.12.6.676","article-title":"Low serum alkaline phosphatase activity and pathologic fracture: case report and brief review of hypophosphatasia diagnosed in adulthood","volume":"12","author":"Khandwala","year":"2006","journal-title":"Endocr Pract."},{"key":"2024020318260091300_bib2","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1148\/radiology.171.2.2539609","article-title":"X-linked hypophosphatemia in adults: prevalence of skeletal radiographic and scintigraphic features","volume":"171","author":"Hardy","year":"1989","journal-title":"Radiology."},{"key":"2024020318260091300_bib3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jbmr.253","article-title":"Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research","volume":"25","author":"Shane","year":"2010","journal-title":"J Bone Miner Res."},{"key":"2024020318260091300_bib4","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1001\/jama.2011.190","article-title":"Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women","volume":"305","author":"Park-Wyllie","year":"2011","journal-title":"JAMA."},{"key":"2024020318260091300_bib5","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1056\/NEJMoa1010650","article-title":"Bisphosphonate use and atypical fractures of the femoral shaft","volume":"364","author":"Schilcher","year":"2011","journal-title":"N Engl J Med."},{"key":"2024020318260091300_bib6","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s00068-009-8237-7","article-title":"Fixation of subtrochanteric fractures in two patients with osteopetrosis using a distal femoral locking compression plate of the contralateral side","volume":"36","author":"Amit","year":"2010","journal-title":"Eur J Trauma Emerg Surg."},{"key":"2024020318260091300_bib7","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1007\/s11999-008-0256-x","article-title":"Case reports: treatment of subtrochanteric and ipsilateral femoral neck fractures in an adult with osteopetrosis","volume":"466","author":"Birmingham","year":"2008","journal-title":"Clin Orthop Rel Res."},{"key":"2024020318260091300_bib8","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1002\/jbmr.308","article-title":"An atypical subtrochanteric femoral fracture from pycnodysostosis: a lesson from nature","volume":"26","author":"Yates","year":"2011","journal-title":"J Bone Miner Res."},{"key":"2024020318260091300_bib9","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/B978-0-12-382040-2.10028-0","volume-title":"Pediatric bone: biology and diseases","author":"Whyte","year":"2012","edition":"3rd edition"},{"key":"2024020318260091300_bib10","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1126\/science.165.3899.1262","article-title":"Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo","volume":"165","author":"Fleisch","year":"1969","journal-title":"Science."},{"key":"2024020318260091300_bib11","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/j.1749-6632.2010.05387.x","article-title":"Physiological role of alkaline phosphatase explored in hypophosphatasia","volume":"1192","author":"Whyte","year":"2010","journal-title":"Ann N Y Acad Sci."},{"key":"2024020318260091300_bib12","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1007\/BF01800216","article-title":"Increased plasma pyridoxa1-5\u2032-phosphate levels before and after pyridoxine loading in carriers of perinatal\/infantile hypophosphatasia","volume":"13","author":"Chodirker","year":"1990","journal-title":"J Inherit Metab Dis."},{"key":"2024020318260091300_bib13","doi-asserted-by":"crossref","first-page":"981","DOI":"10.2106\/00004623-198668070-00004","article-title":"Management of femoral fractures and pseudofractures in adult hypophosphatasia","author":"Coe","year":"1986","journal-title":"J Bone Joint Surg."},{"key":"2024020318260091300_bib14","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1210\/jc.2006-1902","article-title":"Adult hypophosphatasia treated with teriparatide","volume":"92","author":"Whyte","year":"2007","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020318260091300_bib15","first-page":"266","article-title":"Teriparatide treatment in adult hypophosphatasia in a patient exposed to bisphosphonate: a case report","volume":"3","author":"Doshi","year":"2009","journal-title":"Clin Cases Miner Bone Metab."},{"key":"2024020318260091300_bib16","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.jchromb.2005.07.017","article-title":"Use of chlorite to improve HPLC detection of pyridoxal 5\u2032-phosphate","volume":"823","author":"Ericson","year":"2005","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci."},{"key":"2024020318260091300_bib17","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1006\/mgme.2001.3283","article-title":"Denaturing gradient gel electrophoresis analysis of the tissue nonspecific alkaline phosphatase isoenzyme gene in hypophosphatasia","volume":"75","author":"Mumm","year":"2002","journal-title":"Mol Genet Metab."},{"key":"2024020318260091300_bib18","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1097\/00005792-198401000-00002","article-title":"Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms","volume":"63","author":"Fallon","year":"1984","journal-title":"Medicine (Baltimore)."},{"key":"2024020318260091300_bib19","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1001\/archinte.1981.00340060035010","article-title":"Heterogeneity of adult hypophosphatasia. Report of severe and mild cases","volume":"141","author":"Weinstein","year":"1981","journal-title":"Arch Intern Med."},{"key":"2024020318260091300_bib20","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1359\/jbmr.090308","article-title":"Chronic recurrent multifocal osteomyelitis mimicked in childhood hypophosphatasia","volume":"24","author":"Whyte","year":"2009","journal-title":"J Bone Miner Res."},{"key":"2024020318260091300_bib21","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1359\/jbmr.081253","article-title":"Atypical femoral fractures, bisphosphonates and adult hypophosphatasia","volume":"24","author":"Whyte","year":"2009","journal-title":"J Bone Miner Res."},{"key":"2024020318260091300_bib22","first-page":"955","article-title":"Roentgen appearance of the skeleton in osteomalacia and rickets","volume":"91","author":"Steinbach","year":"1964","journal-title":"Am J Roentgenol Radium Ther Nucl Med."},{"issue":"Suppl 1","key":"2024020318260091300_bib23","first-page":"S61","article-title":"A retrospective analysis of all atypical femoral fractures seen in a large California HMO from the years 2007 to 2009","volume":"25","author":"Dell","year":"2010","journal-title":"J Bone Miner Res."},{"key":"2024020318260091300_bib24","doi-asserted-by":"crossref","article-title":"Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy","author":"Otero","DOI":"10.1002\/jbmr.1752"},{"issue":"2","key":"2024020318260091300_bib25","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1385\/BTER:104:2:131","article-title":"Bone-specific alkaline phosphatase activity is inhibited by bisphosphonates: role of divalent cations","volume":"104","author":"Vaisman","year":"2005","journal-title":"Biol Trace Elem Res."},{"issue":"5","key":"2024020318260091300_bib26","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1016\/j.bone.2010.12.033","article-title":"Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features","volume":"48","author":"Giusti","year":"2011","journal-title":"Bone."},{"key":"2024020318260091300_bib27","author":"Mornet"},{"key":"2024020318260091300_bib28","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/humu.1154","article-title":"Twelve novel mutations in the tissue-nonspecific alkaline phosphatase gene (ALPL) in patients with various forms of hypophosphatasia","volume":"18","author":"Taillandier","year":"2001","journal-title":"Hum Mutat."},{"key":"2024020318260091300_bib29","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1359\/jbmr.2003.18.4.624","article-title":"Marrow cell transplantation for infantile hypophosphatasia","volume":"18","author":"Whyte","year":"2003","journal-title":"J Bone Miner Res."},{"key":"2024020318260091300_bib30","doi-asserted-by":"crossref","first-page":"9924","DOI":"10.1073\/pnas.89.20.9924","article-title":"Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia","volume":"89","author":"Henthorn","year":"1992","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2024020318260091300_bib31","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1359\/jbmr.2001.16.12.2313","article-title":"Mutational analysis and functional correlation with phenotype in German patients with childhood-type hypophosphatasia","volume":"16","author":"Orimo","year":"2001","journal-title":"J Bone Miner Res."},{"key":"2024020318260091300_bib32","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/0002-9343(57)90124-9","article-title":"Hypophosphatasia","volume":"22","author":"Fraser","year":"1957","journal-title":"Am J Med."},{"key":"2024020318260091300_bib33","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1469-1809.2011.00642.x","article-title":"A molecular-based estimation of the prevalence of hypophosphatasia in a European population","volume":"75","author":"Mornet","year":"2011","journal-title":"Ann Hum Genet."},{"key":"2024020318260091300_bib34","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1002\/jbmr.527","article-title":"Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density","volume":"27","author":"Nielson","year":"2012","journal-title":"J Bone Miner Res."},{"key":"2024020318260091300_bib35","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1093\/ajcn\/53.3.698","article-title":"Extremely low serum pyridoxal 5\u2032-phosphate in children with familial hypophosphatemic rickets","volume":"53","author":"Reynolds","year":"1991","journal-title":"Am J Clin Nutr."},{"key":"2024020318260091300_bib36","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/0003-2697(77)90510-3","article-title":"Analysis of inorganic pyrophosphate at the picomole level","volume":"83","author":"Cheung","year":"1977","journal-title":"Anal Biochem."},{"key":"2024020318260091300_bib37","first-page":"S225","article-title":"Use of teriparatide in patients with atypical femur fractures (abstract)","volume":"26","author":"Cheung","year":"2011","journal-title":"J Bone Miner Res."},{"key":"2024020318260091300_bib38","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1056\/NEJMoa1106173","article-title":"Enzyme-replacement therapy in life-threatening hypophosphatasia","volume":"366","author":"Whyte","year":"2012","journal-title":"N Engl J Med."}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.1565","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/27\/5\/987\/56561923\/1565_ftp.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/27\/5\/987\/56561923\/1565_ftp.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T10:46:09Z","timestamp":1710326769000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/27\/5\/987-994\/7598477"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,2,9]]},"references-count":38,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2012,2,9]]},"published-print":{"date-parts":[[2012,5,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.1565","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.14001960.15455064","asserted-by":"object"}]},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,5,1]]},"published":{"date-parts":[[2012,2,9]]}}}